Long-Term PFS Benefit With Olaparib in nonBRCA-Mutant Ovarian Cancer More Likely With HRD Positivity

Patients treated with maintenance olaparib (Lynparza) who had platinum-sensitive relapsed ovarian cancer (PSR OC) without a germline BRCA1/2 mutation (non-gBRCAm) and achieved long-term progression-free survival (PFS; n = 67) had homologous recombination deficiency (HRD)-positive tumors more often than those with short-term PFS (n = 65), according to results from the phase 3b OPINION study (NCT03402841).

“Overall, long-term PFS was seen in patients with a wide range of clinical and molecular factors, reinforcing the potential benefit of olaparib in all patients with platinum-sensitive relapsed ovarian cancer without a germline BRCA mutation,” said lead author Stéphanie Lheureux, MD, PHD, a clinical investigator with Princess Margaret Cancer Centre. She presented the findings in a poster during The Society of Gynecologic Oncology (SGO) 2022 Annual Meeting on Women’s Cancer.

Lheureux and colleagues noted that these findings are consistent with previous results showing longer PFS among patients with HRD-positive tumors in the overall population. Additionally, more patients with a long-term PFS achieved a complete response (CR) to their last platinum-based chemotherapy regimen compared with those who had a short-term PFS, 51% vs 18%, respectively.

Investigators sorted patients into the long-term PFS group if they were more than 18 months removed from a PFS event, censored PFS event, or study discontinuation after their first dose, with patients progression-free at analysis also included. Patients who were less than 4 months removed from a PFS event or censored PFS event were considered short-term PFS. Patients with neither long- nor short-term PFS (n = 147) were excluded from the analysis. The data cutoff date was October 2, 2020.

Molecular analyses searched for the presence of tumor BRCA mutation (tBRCAm), somatic BRCA mutation (sBRCAm), and HRD, defined as a genomic instability score of 42 or more and/or tBRCAm. Non-BRCA homologous recombination repair gene mutations (HRRm) was based on a prespecified 13-gene panel, and non-HRR gene mutations were considered. Tumor samples were analyzed using the Myriad myChoice HRD plus assay on archival tissue or fresh biopsy if archival tissue was not available and gBRCAm was detected using the BRACAnalysis CDx assay.

The long-term PFS cohort had a median age of 64 (range, 41-84) compared with 66 (range, 42-84) in the short-term PFS group. Both groups had a median of 2 prior lines of platinum-based chemotherapy and the median times to diagnosis were 3.3 years (range, 1.3-13.4) and 2.85 years (range, 1.2-22.5) in the long-term and short-term groups, respectively.

Most of the patients (70%) in the long-term PFS group had HRD-positive tumors versus 40% of patients in the short-term group. Investigators observed mutations in both tBRCAmand non-BRCA HRRmat a rate of 22% in the long-term PFS group and both at 8% in the short-term group.

The most common non-BRCA HRR genes with a deleterious/suspected deleterious mutation were RAD51D (10%) and RAD51C (7%) among patients with a long-term PFS; only 1 patient in the short-term PFS arm had either of these alterations. Additionally, 37% of patients in the long-term PFS group had TP53-disruptive mutations compared with 49% of the short-term PFS group. The second most common non-BRCA, non-HRR gene in the long-term PFS group following TP53 was NF1 (19%). Most of these patients (92%) also had HRD-positive tumors.

Additional data from the analysis showed that most patients in the long-term (72%) and short-term (65%) PFS groups had a platinum-free interval of 12 months or more. A majority of patients in both groups had stage III disease at diagnosis, 67% and 72%, respectively.

Reference

Lheureux S, Oaknin A, Sikorska M, et al. Clinical and molecular characteristics of patients with short- and long-term progression-free survival in the phase IIIb OPINION study of maintenance olaparib for patients with non-germline BRCA1/BRCA2-mutated platinum-sensitive relapsed ovarian cancer. Presented at: 2022 SGO Annual Meeting on Women’s Cancer; March 18-21, 2022. Phoenix, Arizona. Abstract 306.